title: Preclinical studies on neurobehavioral and neuromuscular effects of cocaine hydrolase gene therapy in mice.
abstract: Cocaine hydrolase gene transfer of mutated human butyrylcholinesterase (BChE) is evolving as a promising therapy for cocaine addiction. BChE levels after gene transfer can be 1,500-fold above those in untreated mice, making this enzyme the second most abundant plasma protein. Because mutated BChE is approximately 70 % as efficient in hydrolyzing acetylcholine as wild-type enzyme, it is important to examine the impact on cholinergic function. Here, we focused on memory and cognition (Stone T-maze), basic neuromuscular function (treadmill endurance and grip strength), and coordination (Rotarod). BALB/c mice were given adeno-associated virus vector or helper-dependent adenoviral vector encoding mouse or human BChE optimized for cocaine. Age-matched controls received saline or luciferase vector. Despite high doses (up to 10(13) particles per mouse) and high transgene expression (1,000-fold above baseline), no deleterious effects of vector treatment were seen in neurobehavioral functions. The vector-treated mice performed as saline-treated and luciferase controls in maze studies and strength tests, and their Rotarod and treadmill performance decreased less with age. Thus, neither the viral vectors nor the large excess of BChE caused observable toxic effects on the motor and cognitive systems investigated. This outcome justifies further steps toward an eventual clinical trial of vector-based gene transfer for cocaine abuse.
authors.affiliation: Mayo Clinic, Rochester, MN, USA.
authors.forename: Vishakantha
authors.initials: V
authors.lastname: Murthy
authors.forename: Yang
authors.initials: Y
authors.lastname: Gao
authors.forename: Liyi
authors.initials: L
authors.lastname: Geng
authors.forename: Nathan
authors.initials: N
authors.lastname: LeBrasseur
authors.forename: Thomas
authors.initials: T
authors.lastname: White
authors.forename: Stephen
authors.initials: S
authors.lastname: Brimijoin
mesh_terms: D000818:Animals; D002091:Butyrylcholinesterase / Q000235:genetics* / Q000378:metabolism; D003042:Cocaine / Q000378:metabolism*; D019970:Cocaine-Related Disorders / Q000628:therapy*; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism; D015316:Genetic Therapy; D018737:Hand Strength; D006801:Humans; D008297:Male; D018782:Maze Learning; D051379:Mice; D008807:Mice, Inbred BALB C; D011597:Psychomotor Performance
chemical_list: D002091:Butyrylcholinesterase; D003042:Cocaine